1. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.
- Author
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Mandula JK, Chang S, Mohamed E, Jimenez R, Sierra-Mondragon RA, Chang DC, Obermayer AN, Moran-Segura CM, Das S, Vazquez-Martinez JA, Prieto K, Chen A, Smalley KSM, Czerniecki B, Forsyth P, Koya RC, Ruffell B, Cubillos-Ruiz JR, Munn DH, Shaw TI, Conejo-Garcia JR, and Rodriguez PC
- Subjects
- Animals, Endoplasmic Reticulum Stress, Mice, Signal Transduction, T-Lymphocytes metabolism, Unfolded Protein Response, eIF-2 Kinase genetics, eIF-2 Kinase metabolism, Interferon Type I metabolism, Neoplasms
- Abstract
Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C
+ CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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